Drug and Chemical Toxicology最新文献

The purpose of this trial was to assess the effects of methylphenidate on the kidney tissues and to investigate the protective effect of adenosine triphosphate (ATP) against possible methylphenidate nephrotoxicity in rats. The rats were separated into; healthy control (HG), methylphenidate (MPHG), ATP (ATPG), and ATP+ methylphenidate (AMPG). The ATPG and AMPG groups were administered ATP 4 mg/kg bw/d, and the HG and MPHG groups received distilled water intraperitoneally. One hour from, ATP and distilled water administration, methylphenidate 10 mg/kg bw/d was applied via oral gavage to the AMPG and MPHG groups once daily for 30 d (1 × 1). Animals were euthanized after 30 d and tissues were collected. The levels of certain oxidant/antioxidant parameters, pro-inflammatory cytokines, and Blood urea nitrogen (BUN) and creatinine levels were measured. Kidneys were also examined histopathologically. ATP inhibited the increase in oxidant and decrease antioxidant levels induced by methylphenidate. The amounts of pro-inflammatory cytokines were increased in methylphenidate-treated kidney tissue compared with the HG and AMPG groups. However, ATP increased oxidative damage markers and cytokines levels close to the healthy group. Serum BUN and creatinine levels increased with methylphenidate but ATP prevented BUN and creatinine from rising in the ATPG and MPHG groups. ATP also reduced the histopathological damage increased by methylphenidate. The potential efficacy of ATP in treating kidney damage induced by methylphenidate use.

Oroxylum indicum possesses promising flavonoid secondary metabolites. However, translation of these compounds into clinical practice for neurological disease treatment is halted as the toxicity and safety profile of the plant extracts are yet to be determined. This study was conducted to assess the acute oral toxicity and subacute neurotoxicity that could be imposed by the flavonoid-enriched fraction (FEF) extracted from O. indicum leaves, by strictly following the procedures set in Organization for Economic Co-operation and Development (OECD) Guidelines No.420 and 424. It was found that at the highest dosage (2000 mg/kg b.wt), no death or toxicity-related behavioral changes were observed. No significant alteration in hematological and serum biochemical parameters beyond the standard laboratory range was observed. Detailed histopathological examination, as verified by clinical pathologist, revealed absence of detectable inflammation, changes in any macroscopic and microscopic tissue abnormalities in all vital organ of the treated rats. Moreover, neurological functional test of rats treated with repeated doses of FEF for 28 d also showed absence of neurological abnormality, suggesting negative long term side effects of this fraction on the animal. In conclusion, this study presented valuable pre-clinical safety validation of a high-quality herbal medicinal product, setting the foundation for its future application in clinical setting.

Cisplatin-induced nephrotoxicity, a major limitation of this chemotherapeutic agent, involves oxidative stress, inflammation, and apoptosis. This study investigated the potential renoprotective effects of humic acid in a rat model of cisplatin-induced nephrotoxicity. Forty-two male Wistar rats were assigned to six groups: control, humic acid, cisplatin, cisplatin + humic acid 10 mg/kg, cisplatin + humic acid 20 mg/kg, and cisplatin + humic acid 40 mg/kg. On day 7, the rats were sacrificed, and cardiac blood and kidneys were collected for biochemical and histopathological examinations. Humic acid administration significantly attenuated the cisplatin-induced increases in renal TNF-α and NF-κB levels, indicating a reduction in inflammation. Humic acid also ameliorated histopathological damage, including Bowman's capsule dilatation, tubular cell degeneration, and hemorrhage. However, humic acid did not significantly alter oxidative stress parameters or caspase-3 levels. Humic acid demonstrates a protective effect against cisplatin-induced nephrotoxicity in rats, primarily by mitigating the inflammatory response. While HA's beneficial effects on oxidative stress and apoptosis were limited in this study, its ability to reduce inflammation highlights its potential as a therapeutic strategy to mitigate cisplatin-induced kidney injury.

Although atomoxetine, a selective norepinephrine reuptake inhibitor, is widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD), there is limited data on its cytogenetic effects. This study aimed to investigate the cytotoxicity and genotoxicity of atomoxetine in vivo and silico. Chromosome aberration and micronucleus assays were used to analyze the genotoxic effect of atomoxetine in human peripheral blood lymphocytes under culture conditions. The mitotic index was assessed for cytotoxic potential. For the docking analysis, DNA receptor (1BNA) was prepared with ChimeraX, and the Atomoxetine molecule was optimized by Avogadro2.0 software. In silico molecular docking analysis was carried out utilizing SwissDock online platform. The results obtained were visualized using ChimeraX and Pymol software. Atomoxetine doses of 9.6 µg/mL (equal to about 1.2 mg/kg as a maintenance dose), 14.4 µg/mL (equal about to 1.8 mg/kg as the highest dose systematically tested), 48.0 µg/mL (equal about to 6 mg/kg as five times the maintenance dose) and 96.0 µg/mL (equal about to 12 mg/kg as ten times the maintenance dose) were analyzed. The findings clearly indicate that atomoxetine has no genotoxic effect at the therapeutic dose. However, we observed genotoxic effects at 48.0 and 96.0 µg/mL doses. No strong binding affinity occurs in silico analyses. As one of the initial inquiries into the in silico and in vivo appraisal of atomoxetine's genotoxic impacts, the research has established that atomoxetine does not significantly affect the frequency of chromosomal damage or micronucleus formation. Genotoxic effects should be kept in mind at doses above clinical practice.

The aim of this study was to determine the antidotal potential of the chlorinated oxime K870 compared to obidoxime, as a monotherapy and in combination with atropine, in paraoxon (POX)-poisoned rats. The treatment doses of oximes were chosen as 20% of their LD₅₀ values. The protective ratio (PR) of oxime K870 with atropine was significantly higher than that of obidoxime with atropine (68.8 and 125.0, respectively). In the biochemical part of the experiment POX subcutaneously (s.c.) (0.75% LD₅₀) was administered and followed by oxime K870 or obidoxime i.m. 1 min later. Acetylcholinesterase (AChE) activity was determined spectrophotometrically in cerebrum, cerebellum, brainstem, diaphragm, and erythrocytes. Carboxylesterase activity was determined in plasma and liver. Both oximes successfully reactivated AChE in brain (cerebrum, cerebellum, and brainstem), diaphragm and erythrocytes, but the oxime K870 performed better than obidoxime. Both oximes reactivated carboxylesterase, obidoxime better in plasma and oxime K870 better in liver. In conclusion, the oxime K870, when co-administered with atropine, is a more effective antidote than the obidoxime-atropine combination in POX-poisoned rats.

Cyclophosphamide is a key component of numerous chemotherapeutic protocols, demonstrating broad-spectrum efficacy against various malignancies and non-cancerous conditions. This review examines CPM's metabolic pathways, therapeutic applications, and its resulting organ-specific toxicities. Despite its clinical benefits in treating nephrotic syndrome, encephalomyelitis, breast cancer, ovarian cancer, and other diseases, CPM is associated with significant adverse effects on the kidneys, liver, heart, lungs, and intestines. The discussion delves into the molecular mechanisms underlying these toxicities, highlighting dysregulation in key signaling pathways, including Nrf2, NF-κB, MAPK/ERK, and AKT. In addressing these challenges, recent studies have identified various herbal drugs and phytochemicals capable of mitigating CPM-induced toxicity. Notable compounds such as cinnamaldehyde, baicalin, quercetin, and curcumin have demonstrated protective effects. Integrating these herbal formulations with CPM therapy is proposed to enhance patient safety and treatment efficacy. This review underscores the influence of CPM on apoptosis and inflammation pathways, which lead to alterations in organ-specific biomarkers. Phytochemicals may exert protective effects by restoring disrupted signaling pathways and normalizing altered biomarkers. The compilation of phytochemicals presented in this review serves as a valuable resource for researchers exploring other herbal products with potential protective effects against CPM toxicity. A significant gap in the current literature is the lack of clinical trials evaluating phytochemicals that mitigate CPM toxicity in vivo. Rigorous clinical studies are necessary to establish the efficacy and safety of herbal formulations in cancer treatment. Such research will clarify the role of natural remedies in complementing conventional therapies, ultimately improving patient outcomes.

Daily contact with considerable amounts of polystyrene nanoparticles (PSNPs) may cause harmful effects on the living organisms, through mechanisms that are not fully understood. The study aimed to evaluate the cytotoxic and genotoxic effects of PSNPs (size 200 nm and 40 nm) in mesenchymal stem cells (MSCs). In order to estimate cellular uptake and retention of nanoplastics, PSNP-treated cells have been analyzed by transmission electron microscopy. For assessing morphology and viability of MSCs after PSNP treatment at two environmentally relevant doses (0.47 and 4.7 μl/ml) for 24 hours, HE and Giemsa staining were performed. Annexin V‑FITC/PI assay was used to quantify PSNPs-mediated cell death. Genotoxicity of PSNPs was evaluated by Comet test. The capacity of PSNPs to trigger the production of free radicals in MSCs was also evaluated. TEM confirmed endocytosis of PSNPs. Decreased cell volume, nuclear hyperchromatism, edge aggregation, and formation of densely stained apoptotic bodies, indicated that PSNP-treated MSCs undergo apoptosis. The presented data showed that both concentration of PS particles significantly increased early apoptotic cell death in comparison to untreated cells. Moreover, both doses of PSNPs significantly increased the genetic damage index in MSCs in dose-dependent manner. In conclusion, PSNPs penetrate, accumulate and induce cytotoxic and genotoxic damage in MSCs.

Although lithium (LIT) therapy is key in managing bipolar disorder long-term, prolonged use significantly contributes to acquired Nephrogenic Diabetes Insipidus (NDI). This study examined whether combining Silymarin (SIL) with Vitamin C (Vit C) enhances protection against lithium-induced nephrotoxicity in rats, comparing their individual antioxidant effects as well. Rats subjected to Li exposure were provided with a standard commercial diet supplemented with 80 mmol LiCl per kilogram for 28 days. Concurrently, SIL and Vit C were administered orally at dosages of 200 and 100 mg/kg body weight, respectively, throughout the 28 days. The study assessed levels of reactive oxygen species (ROS), glutathione (GSH), and malondialdehyde (MDA), as well as the enzyme activity of superoxide dismutase (SOD), to evaluate the protective effects of SIL and Vit C against oxidative stress. Aquaporin-2 (AQP2) levels in kidney tissues were evaluated using immunohistochemistry and ELISA. Serum and urine parameters (sodium, potassium, creatinine, blood urea nitrogen [BUN], and urea) and serum lithium levels were also measured. Lithium-induced nephrotoxicity showed increased renal toxicity markers and decreased antioxidant enzyme activity. SIL administration significantly reduced markers of kidney tissue toxicity, increased antioxidant enzyme activities, regulated the aforementioned physiological parameters in blood and urine, and downregulated AQP2 expression in the kidney. However, Vit C administration did not demonstrate a significant protective effect against lithium-induced renal toxicity. These findings indicate that SIL effectively protects against lithium-induced nephrotoxicity, whereas Vitamin C does not exhibit this protective effect.

Aflatoxin B₁ (AFB1) and fumonisin B₁ (FB1) are toxic secondary products of fungi that frequently contaminate staple crops in resource-limited settings. Antenatal AFB1 and FB1 exposure may cause adverse birth outcomes. We conducted a retrospective substudy nested in a case-control cohort of HIV-infected and HIV-uninfected women ≥20 weeks gestation from Harare, Zimbabwe. Urinary aflatoxin M₁ (AFM1) and FB1, biomarkers of AFB1 and FB1 exposure, respectively, were quantified in random antenatal urine via ELISA and grouped into tertiles. The adverse birth outcomes considered were low birth weight, preterm birth (PTB), small for gestational age, stillbirth, birth defects, neonatal death, neonatal jaundice and perinatal death (PD). We evaluated any associations between adverse birth outcomes and exposure to AFB1, FB1, or the AFB1-FB1 combination via a multivariable logistic regression controlled for potential confounders. We enrolled 94 HIV-infected and 81 HIV-uninfected women. In HIV-infected, AFM1 was detected in 46/94 (49%), and FB1 was detected in 86/94 (91%). In HIV-uninfected, AFM1 was detected in 48/81 (59%), and FB1 was detected in 74/81 (91%). Among all women, AFM1 tertile 3 was associated with PD (OR: 6.95; 95% CI: 1.21-39.78). In the same population, AFM1 tertiles 2 (OR: 13.46; 95% CI: 1.20-150.11) and 3 (OR: 7.92; 95% CI: 1.08-58.19) were associated with PTB. In HIV-infected, AFM1 tertile 2 was associated with PTB (OR: 64.73; 95% CI: 2.37-177.93). Our results revealed an association between AFB1 exposure and PD and PTB in women, including those infected with HIV. Public health and nutrition measures are necessary to mitigate mycotoxins.

Podocyte injury is a major biomarker of primary glomerular disease that leads to massive proteinuria and kidney failure. Ginsenoside Rk1, a substance derived from ginseng, has several pharmacological activities, such as anti-apoptotic, anti-inflammatory, and antioxidant effects. In this study, our goal is to investigate the roles and mechanisms of ginsenoside Rk1 in podocyte injury and acute kidney injury (AKI). C57BL/6 mice were intraperitoneally injected with 10 mg/kg LPS to mimic AKI-like conditions in vivo. One hour after the LPS challenge, ginsenoside Rk1 (10 mg/kg or 20 mg/kg) or vehicle was orally administered into mice every 6 h until sacrifice at 24 h. Renal functions were assessed by measuring blood urea nitrogen and creatinine. Renal histological changes were examined by hematoxylin and eosin staining. The production of proinflammatory cytokines in kidney tissues was evaluated by RT-qPCR and western blotting. A conditionally immortalized mouse MPC-5 podocyte cell line was treated with LPS and ginsenoside Rk1. Viability and apoptosis of MPC-5 cells were estimated by CCK-8 and flow cytometry. Western blotting was also conducted to measure the protein levels of apoptosis-related and pathway-related genes. The results of abovementioned experiments revealed that Ginsenoside Rk1 ameliorated LPS-stimulated podocyte apoptosis in vitro and relieved renal dysfunctions and inflammatory response in LPS-induced AKI mice. Mechanistically, ginsenoside Rk1 inactivated the JAK2/STAT3 and NF-κB pathways in LPS-treated podocytes and mice. In conclusion, this study shows that Ginsenoside Rk1 attenuates LPS-induced renal dysfunctions and inflammatory response in mice and LPS-induced podocyte apoptosis in vitro through inactivating the NF-κB and JAK2/STAT3 pathways.